Increased Medial Temporal Tau Positron Emission Tomography Uptake in the Absence of Amyloid-β Positivity

Abstract

ImportanceAn increased tau positron emission tomography (PET) signal in the medial temporal lobe (MTL) has been observed in older individuals in the absence of amyloid-β (Aβ) pathology. Little is known about the longitudinal course of this condition, and its association with Alzheimer disease (AD) remains unclear.ObjectiveTo study the pathologic and clinical course of older individuals with PET-evidenced MTL tau deposition (TMTL+) in the absence of Aβ pathology (A−), and the association of this condition with the AD continuum.Design, Setting, and ParticipantsA multicentric, observational, longitudinal cohort study was conducted using pooled data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain Study (HABS), and the AVID-A05 study, collected between July 2, 2015, and August 23, 2021. Participants in the ADNI, HABS, and AVID-A05 studies (N = 1093) with varying degrees of cognitive performance were deemed eligible if they had available tau PET, Aβ PET, and magnetic resonance imaging scans at baseline. Of these, 128 participants did not meet inclusion criteria based on Aβ PET and tau PET biomarker profiles (A+ TMTL−).ExposuresTau and Aβ PET, magnetic resonance imaging, cerebrospinal fluid biomarkers, and cognitive assessments.Main Outcomes and MeasuresCross-sectional and longitudinal measures for tau and Aβ PET, cortical atrophy, cognitive scores, and core AD cerebrospinal fluid biomarkers (Aβ42/40 and tau phosphorylated at threonine 181 p-tau181 available in a subset).ResultsAmong the 965 individuals included in the study, 503 were women (52.1%) and the mean (SD) age was 73.9 (8.1) years. A total of 51% of A− individuals and 78% of A+ participants had increased tau PET signal in the entorhinal cortex (TMTL+) compared with healthy younger (aged <39 years) controls. Compared with A− TMTL−, A− TMTL+ participants showed statistically significant, albeit moderate, longitudinal (mean [SD], 1.83 [0.84] years) tau PET increases that were largely limited to the temporal lobe, whereas those with A+ TMTL+ showed faster and more cortically widespread tau PET increases. In contrast to participants with A+ TMTL+, those with A− TMTL+ did not show any noticeable Aβ accumulation over follow-up (mean [SD], 2.36 [0.76] years). Complementary cerebrospinal fluid analysis confirmed longitudinal p-tau181 increases in A− TMTL+ in the absence of increased Aβ accumulation. Participants with A− TMTL+ had accelerated MTL atrophy, whereas those with A+ TMTL+ showed accelerated atrophy in widespread temporoparietal brain regions. Increased MTL tau PET uptake in A− individuals was associated with cognitive decline, but at a significantly slower rate compared with A+ TMTL+.Conclusions and RelevanceIn this study, individuals with A− TMTL+ exhibited progressive tau accumulation and neurodegeneration, but these processes were comparably slow, remained largely restricted to the MTL, were associated with only subtle changes in global cognitive performance, and were not accompanied by detectable accumulation of Aβ biomarkers. These data suggest that individuals with A− TMTL+ are not on a pathologic trajectory toward AD.

Explaining variability in early stages of [18F]‐flortaucipir tau‐PET binding: Focus on sex differences

“…16,42 This is further supported by a recent imaging study, which showed subtle longitudinal changes in tau-PET among individuals who were Aβ negative but exhibited elevated medial temporal tau-PET signal. 14 Importantly, we identified significant interactions between sex and Aβ burden on tau-PET signal within temporoparietal brain regions. These interactions consistently indicated that, in regions typically associated with early AD-related tau pathology, females exhibited higher tau-PET signal for a given burden of Aβ than males.…”

“…12,13 Advanced age is another factor linked to increased tau-PET burden. Some individuals exhibit elevated tau-PET signal, especially in the medial temporal lobe regions, in the absence of significant Aβ-PET burden, 14,15 which may be related to primary age-related tauopathy (PART), a condition neuropathologically characterized by neurofibrillary tangles without substantial Aβ pathology. 16 Some evidence also suggests, that agerelated tau accumulation is not only confined to medial temporal regions, but can also be observed in several neocortical regions.…”

The Relationship between p-tau217, p-tau231, and p-tau205 in the Human Brain Is Affected by the Cellular Environment and Alzheimer’s Disease Pathology

“…None of the co-localized p-tau fraction areas were significantly altered in the EC of Cohort II when comparing AD int or AD high to PART (p = 0.67. p = 0.16 and p = 0.07), but all three were significantly higher in the ITG of AD high compared to PART (p = 0.0001, p = 0.0005, and p = 0.0005, respectively) (Figure 4F-H). Again, these findings were expected, since tauopathy in EC is one of the characteristics of PART, while less tauopathy is expected to be found in the ITG of these patients [29,30].…”

The diagnostic and prognostic value of tau‐PET in amnestic MCI with different FDG‐PET subtypes

“…We found only four cases with a minimal tau load in MTL, likely due to age‐related changes. 45 , 46 The association between amyloid positivity and a diagnosis of AD dementia becomes weaker with aging, 47 and there is autopsy evidence for significant amyloid deposition in aged brains of people without antemortem dementia. 48 Concerning tau, our results fit with Botha et al.…”